5-HT2A receptor
The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and functions as a G protein-coupled receptor. It is a cell surface receptor that activates multiple intracellular signalling cascades.
Like all 5-HT2 receptors, the 5-HT2A receptor is coupled to the Gq/G11 signaling pathway. It is the primary excitatory receptor subtype among the serotonin-responsive GPCRs. The 5-HT2A receptor was initially noted for its central role as the primary target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. It later regained research prominence when found to mediate, at least in part, the effects of many antipsychotic drugs, particularly atypical antipsychotics.
History
The serotonin receptors were split into two classes by John Gaddum and Picarelli in 1957 when it was discovered that some of the serotonin-induced changes in the gut could be blocked by morphine, while the remainder of the response was inhibited by dibenzyline, leading to the naming of M and D receptors, respectively. The 5-HT2A receptor is thought to correspond to what was originally described as D subtype of serotonin receptors by Gaddum and Picarelli.In the era before molecular cloning, when radioligand binding and displacement was the only major tool, spiperone and LSD were shown to label two different 5-HT receptors, and neither of them displaced morphine, leading to naming of the 5-HT1, 5-HT2 and 5-HT3 receptors, corresponding to high affinity sites from LSD, spiperone and morphine, respectively. Later, it was shown that the 5-HT2 receptor was very close to the 5-HT1C receptor and they were thus were grouped together, renaming the 5-HT2 receptor into 5-HT2A receptor and the 5-HT1C receptor into the 5-HT2C receptor. Thus, the 5-HT2 receptor family is composed of three separate molecular entities: the 5-HT2A, the 5-HT2B and the 5-HT2C receptors.
The serotonin 5-HT2A receptor was identified via radioligand binding in 1978 by Leysen and colleagues. Peroutka and Snyder identified two distinct serotonin receptors and named them the 5-HT1 receptor and 5-HT2 receptor in 1979. Later, both of these receptors were found to have several subtypes, including the serotonin 5-HT2A receptor. The serotonin 5-HT2A receptor was characterized as a membrane protein by Wouters and colleagues in 1985. The gene encoding the rat serotonin 5-HT2A receptor, HTR2A, was cloned in 1988 by Pritchett and colleagues. The human gene was cloned by Branchek and colleagues in 1990.
Gene
The 5-HT2A receptors is coded by the HTR2A gene. In humans the gene is located on chromosome 13. The gene has previously been called just HTR2 until the description of two related genes HTR2B and HTR2C. Several interesting polymorphisms have been identified for HTR2A: A-1438G, C102T, and His452Tyr. Many more polymorphisms exist for the gene. A 2006 paper listed 255.Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.
Human HTR2A gene is thought to consist of 3 introns and 4 exons and to overlap with human gene HTR2A-AS1 which consists of 18 exons. There are over 200 organisms that have orthologs with the human HTR2A. Currently, the best documented orthologs for HTR2A gene are the mouse, and zebrafish. There are 8 paralogs for the HTR2A gene. The HTR2A gene is known to interact and activate G-protein genes such as GNA14, GNAI1, GNAI3, GNAQ, and GNAZ. These interactions are critical for cell signaling and homeostasis in many organisms.
In human brain tissue, regulation of HTR2A varies depending on the region: frontal cortex, amygdala, thalamus, brain stem and cerebellum. In a paper from 2016, they found that HTR2A undergoes a variety of different splicing events, including utilization of alternative splice acceptor sites, exon skipping, rare exon usage, and intron retention.
Transcriptional regulation
There are a few mechanisms of regulation for HTR2A gene such regulated by DNA methylation at particular transcript binding sites. Another mechanism for the correct regulation of gene expression is achieved through alternative splicing. This is a co-transcriptional process, which allows the generation of multiple forms of mRNA transcript from a single coding unit and is emerging as an important control point for gene expression. In this process, exons or introns can be either included or excluded from precursor-mRNA resulting in multiple mature mRNA variants. These mRNA variants result in different isoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells. One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5' UTR.Tissue distribution
5-HT2A is expressed widely throughout the central nervous system.It is expressed near most of the serotonergic terminal rich areas, including neocortex and the olfactory tubercle. Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes, working memory, and attention by enhancing glutamate release followed by a complex range of interactions with the 5-HT1A, GABAA, adenosine A1, AMPA, mGluR2/3, mGlu5, and OX2 receptors. In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer, and in the Purkinje cells.
In the periphery, it is highly expressed in platelets and many cell types of the cardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT2A mRNA expression has been observed in human monocytes. Whole-body distribution of the 5-HT2A/2C receptor agonist, Cimbi-36 show uptake in several internal organs and brown adipose tissue, but it is not clear if this represents specific 5-HT2A receptor binding.
Structure
The 5-HT2A receptor is a member of the class A G protein-coupled receptor family, characterized by seven transmembrane α-helices connected by extracellular and intracellular loops. Its ligand-binding pocket is composed of two adjacent subpockets: the orthosteric binding pocket and an extended binding pocket, with a unique side-extended cavity near the orthosteric site that distinguishes it from related receptors. Ligands are anchored primarily through a conserved aspartate residue that interacts with their charged amine groups, while additional interactions involve hydrophobic contacts and hydrogen bonds with residues in both the OBP and EBP. Structural studies reveal that the receptor undergoes significant conformational changes upon activation, particularly in transmembrane helices 3 and 6, which facilitate G protein coupling and signal transduction. The extracellular ligand-binding pocket is closed by a flexible "lid," and the intracellular region includes a short helix stabilized by π-stacking interactions, both of which contribute to the receptor's dynamic conformational landscape. These structural features underlie the receptor's ability to recognize diverse ligands and mediate complex signaling behaviors.The cryo-EM structures of the serotonin 5-HT2A receptor with a variety of serotonin 5-HT2A receptor agonists, including the tryptamines serotonin, psilocin, and dimethyltryptamine , the lysergamides LSD and 2-bromo-LSD , and the phenethylamines mescaline and RS130-180, have been solved and published by Bryan Roth and colleagues.